Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands, major histocompatibility complex class I chain-related proteins A and B
Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands, major histocompatibility complex class I chain-related proteins A and B
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DOI：
10.1128/jvi.02251-07
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发表时间：
2008-05-01
影响因子：
5.4
通讯作者：
Wilkinson, Gavin W. G.
中科院分区：
文献类型：
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作者：
McSharry, Brian P.;Burgert, Hans-Gerhard;Wilkinson, Gavin W. G.
腺病毒 (Ad) 早期转录单元 3 (E3) 编码多种免疫破坏功能，这些功能被认为有助于促进感染的建立和持续。事实上，E3/19K 抑制 I 类 HLA (HIA-I) 转运至细胞表面的能力，从而阻止肽呈递给 CD8(+) T 细胞，长期以来一直被认为是病毒免疫逃避的范例。然而，HLA-I 下调有可能使 Ad 感染的细胞容易受到自然杀伤 (NK) 细胞的识别。此外，立即早期 Ad 基因 E1A 的表达与关键 NK 细胞激活受体 NKG2D 配体的有效诱导相关。在这里，我们表明，虽然野生型 Ad 的感染增强了 NKG2D 配体、主要组织相容性复合物 I 类链相关蛋白 A 和 B（MICA 和 MICB）的合成，但它们在细胞表面的表达受到积极抑制。 MICA 和 MICB 均以未成熟的内切糖苷酶 H 敏感形式保留在内质网内。通过分析一系列携带 E3 基因区域突变版本的细胞系和病毒，E3/19K 被确定为负责这种活性的基因。 E3/19K 内隔离 MICA/B 和 HLA-I 所需的结构要求相似。在功能测定中，E3/19K 的缺失使 Ad 感染的细胞对 NK 细胞识别更加敏感。我们报告了腺病毒科中的第一个 NK 逃避功能，并描述了 E3/19K 的新功能。因此，E3/19K 具有双重功能：抑制 T 细胞识别和 NK 细胞激活。
The adenovirus (Ad) early transcription unit 3 (E3) encodes multiple immunosubversive functions that are presumed to facilitate the establishment and persistence of infection. Indeed, the capacity of E3/19K to inhibit transport of HLA class I (HIA-I) to the cell surface, thereby preventing peptide presentation to CD8(+) T cells, has long been recognized as a paradigm for viral immune evasion. However, HLA-I downregulation has the potential to render Ad-infected cells vulnerable to natural killer (NK) cell recognition. Furthermore, expression of the immediate-early Ad gene E1A is associated with efficient induction of ligands for the key NK cell-activating receptor NKG2D. Here we show that while infection with wild-type Ad enhances synthesis of the NKG2D ligands, major histocompatibility complex class I chain-related proteins A and B (MICA and MICB), their expression on the cell surface is actively suppressed. Both MICA and MICB are retained within the endoplasmic reticulum as immature endoglycosidase H-sensitive forms. By analyzing a range of cell lines and viruses carrying mutated versions of the E3 gene region, E3/19K was identified as the gene responsible for this activity. The structural requirements within E3/19K necessary to sequester MICA/B and HLA-I are similar. In functional assays, deletion of E3/19K rendered Ad-infected cells more sensitive to NK cell recognition. We report the first NK evasion function in the Adenoviridae and describe a novel function for E3/19K. Thus, E3/19K has a dual function: inhibition of T-cell recognition and NK cell activation.